Alzheimer's disease (AD) is characterized by the progressive loss of cognitive function and the accumulation of amyloid beta (Aβ) plaques in regions associated with learning and memory. While Aβ plaques were once thought to play a central role in the pathogenesis of AD, a growing body of evidence suggests that soluble oligomeric species of Aβ may be responsible for the disease-associated neuronal dysfunction and cognitive decline (Walsh & Selkoe (2004) Protein Pept. Lett. 11:213-228; Selkoe (2008) Behavioral Brain Res. 192:106-113; Sakano & Zako (2010) FEBS J. 277:1348-58). Soluble, globular, non-fibrillar oligomeric species of Aβ, also referred to Aβ-derived diffusible ligands (ADDLs; Lambert et al. (1998) Proc. Natl. Acad. Sci. USA 95:6448-53) or toxic soluble Aβ oligomers (Walsh, et al. (2002) Nature 416:535-539; Selkoe (2008) Handb. Clin. Neurol. 89:245-60), are abundant in AD, but not normal brains (McLean, et al. (1999) Ann. Neurol. 46:860-866; Gong, et al. (2003) Proc. Natl. Acad. Sci. USA 100:10417-10422). In vitro studies have shown that ADDLs, isolated from AD brain or synthetic preparations, bind to a subpopulation of cortical and hippocampal neurons (Gong, et al. (2003) supra; Klein, et al. (2004) Neurobiol. Aging 25:569-580; Lacor, et al. (2004) J. Neurosci. 24:10191-10200; Shughrue, et al. (2010) Neurobiol. Aging 31:189-202), while little or no binding is detected with fibrillar or monomer Aβ preparations (Lacor, et al. (2004) supra; Hepler, et al. (2006) Biochemistry 45:15157-15167). More specifically, ADDL binding has been demonstrated to be localized to the synapses of hippocampal neurons (Rammes, et al. (2011) Neuropharmacol. 60:982).
Furthermore, ADDL binding to neurons can be attenuated with both polyclonal (Gong, et al. (2003) supra) and monoclonal antibodies (Lee, et al. (2006) J. Biol. Chem. 281:4292-4299; De Felice, et al. (2007) Neurobiol. Aging 29:1334-1347; Shughrue, et al. (2010) supra) generated against ADDLs.
In rodent models, the central administration of ADDLs induces deficits in rodent long-term potentiation (LTP) and memory formation (Walsh, et al. (2002) supra; Cleary, et al. (2004) Nat. Neurosci. 8:79-84; Klyubin, et al. (2005) Nat. Med. 11:556-561). The effect of oligomers on LTP was attenuated when ADDLs were co-administered with an anti-Aβ antibody or administered to animals that were vaccinated with the Aβ peptide (Rowan, et al. (2004) Exp. Gerontol. 39:1661-1667). In a transgenic model of AD, such as transgenic mice that produce human amyloid precursor protein (hAPP), age-associated cognitive deficits have been observed with elevated ADDL levels (Westerman, et al. (2002) J. Neurosci. 22:1858-1867; Ashe (2005) Biochem. Soc. Trans. 33:591-594; Lee, et al. (2006) supra; Lesne, et al. (2006) supra). When hAPP mice were treated with an anti-Aβ oligomer antibody, a significant improvement in cognitive performance was observed without a concomitant decrease in Aβ plaque load (Lee, et al. (2006) supra). Together these findings suggest that ADDLs, and not Aβ plaques, are primarily responsible for cognitive impairment and that the use of anti-ADDL antibodies may prove efficacious in the treatment of AD. See also, U.S. Pat. Nos. 7,731,962, 7,780,963; WO 2007/050359; US 2007/0218499, WO 2006/014478; U.S. Pat. No. 7,700,099; US 2008/01758835, WO 2006/055178; and U.S. Pat. No. 7,811,563.
Accordingly, there is a need for ADDL-selective therapeutic antibodies for the prevention and treatment of AD. The present invention meets this need.